The long-term goal of the principal investigator is to investigate the mechanisms leading to the development of human liver tumors. The proposed research plan is a mechanistic-based approach that will allow the principal investigator to establish that gain-of-function of the Ron receptor tyrosine kinase is sufficient for hepatic tumor formation. Our preliminary data shows that Ron receptor is over-expressed in a large percentage of human hepatoblastomas, the most common hepatic tumor in the pediatric population, and experimentally, that Ron receptor gain-of-function in hepatocytes in vivo (e.g. in transgenic mice with liver-specific over-expression of Ron receptor) and in vitro (e.g. in stable Hepa1-6 cell transfectants) leads to induction of proliferating hepatic tumor nodules and increased cellular growth rates, respectively. Activation of the (-catenin signaling pathway is a significant finding in human hepatic tumors, and our preliminary data suggests that Ron receptor activates this signaling pathway in cell cultures in vitro and in human hepatic tumors. Based on this preliminary data and supportive evidence in the literature, we hypothesize that gain-of- function of the Ron receptor tyrosine kinase leads to hepatic tumorigenesis, mediated by activation of (-catenin. To test this hypothesis, the aims of this proposal are to: 1) establish that gain-of-function of the Ron receptor in hepatocytes in vitro leads to the acquisition of tumorigenic properties, mediated by activation of the (-catenin signaling cascade. We will pursue this aim by assessing hepatocyte transfectants which over-express wild type or constitutively active Ron receptor for transforming and tumorigenic properties;2) establish that over-expression of Ron receptor in the liver causes hepatic tumor formation. This aim involves characterizing hepatic tumor nodules that develop in transgenic mice which over-express wild type Ron receptor in the liver for properties associated with hepatic tumorigenesis, and 3) determine if gain-of-function of the Ron receptor in human hepatic tumors is associated with activation of the (-catenin signaling cascade. This will be determined by analyzing both hepatoblastoma and hepatocellular carcinoma specimens for Ron receptor over-expression and -activation, and recruitment of the (-catenin signaling cascade. The successful execution of the proposed experiments will establish that gain-of-function of the Ron receptor in hepatocytes is a novel mechanism for hepatic tumor formation worthy of further, detailed investigation.